Cpeb4-Mediated Translational Regulatory Circuitry Controls Terminal Erythroid Differentiation

• Cpeb4 is induced by Gata1/Tal1 and is required for terminal erythropoiesis
• Cpeb4 interacts with eIF3 to repress mRNA translation in erythroid cells
• Cpeb4 binds a large group of mRNAs, including its own, in erythroid cells
• Maintaining Cpeb4 level within a range is required for terminal erythropoiesis

SummaryWhile we have considerable understanding of the transcriptional networks controlling mammalian cell differentiation, our knowledge of posttranscriptional regulatory events is very limited. Using differentiation of primary erythroid cells as a model, we show that the sequence-specific mRNA-binding protein Cpeb4 is strongly induced by the erythroid-important transcription factors Gata1 and Tal1 and is essential for terminal erythropoiesis. By interacting with the translation initiation factor eIF3, Cpeb4 represses the translation of a large set of mRNAs, including its own mRNA. Thus, transcriptional induction and translational repression combine to form a negative feedback loop to control Cpeb4 protein levels within a specific range that is required for terminal erythropoiesis. Our study provides an example of how translational control is integrated with transcriptional regulation to precisely control gene expression during mammalian cell differentiation.